Piperazine derivatives as 5-HT1A ligands

ABSTRACT

Piperazine derivatives of formula (I) and their salts are 5-HT 1A  binding agents and may be used, for example, as anxiolytics. In the formula, R, R 2  and R 4  are hydrogen or lower alkyl, R 1  is mono- or bicyclic aryl or heteroaryl, R 3  is lower alkyl or cycloalkyl, A is an alkylene chain and X is --CO--. --CR 5  OH-- (where R 5  is hydrogen, lower alkyl or cycloalkyl), --S--, --SO-- or --SO 2  -- or X can also be --(CH 2 ) n  -- (where n is 0, 1 or 2) when R 3  is cycloalkyl. ##STR1##

This application is a 371 of PCT/GB 94/00539 filed Mar. 17, 1994.

This invention relates to piperazine derivatives, to processes for theirpreparation, to their use and to pharmaceutical compositions containingthem. The novel compounds act upon the central nervous system by bindingto 5-HT receptors (as more fully explained below) and hence can be usedas medicaments for treating human and other mammals.

The novel compounds of the invention are those of the general formula##STR2## and the pharmaceutically acceptable acid addition saltsthereof.

In formula (I):

R represents hydrogen or one or two same or different (lower)alkylgroups

R¹ is a mono- or bicyclic aryl or heteroaryl radical

R² is hydrogen or lower alkyl

R³ is lower alkyl or cycloalkyl

R⁴ is hydrogen or lower alkyl

A is an alkylene chain of 1 to 3 carbon atoms optionally substituted byone or more lower alkyl groups and

X is --CO--. --CR⁵ OH-- (where R⁵ is hydrogen, lower alkyl orcycloalkyl) --S--, --SO-- or --SO₂₋ or X can also be --(CH₂)_(n) --(where n is 0, 1 or 2) when R³ is cycloalkyl.

The term "lower" as used herein means that the radical referred tocontains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl,propyl, isopropyl, butyl, tert.-butyl, pentyl and isopentyl. Acycloalkyl group preferably contains 3 to 7 carbon atoms. Examples ofthe cycloalkyl group R³ include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

When used herein "aryl" means an aromatic radical having 6 to 12 carbonatoms (eg phenyl or naphthyl) which optionally may be substituted by oneor more substituents. Preferred substituents are lower alkyl, loweralkoxy (eg methoxy, ethoxy, propoxy, butoxy), halogen, halo(lower)alkyl(eg trifuoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl,amino, (lower)alkylamino or di(lower)alkylamino substituents. Twosubstituents on the aromatic ring may be connected together to formanother ring system. For example R¹ may be a bicyclic oxygen-containingradical of the formula ##STR3## wherein the heterocyclic ring containingthe oxygen atom contains a total of 5 to 7 ring members, saidheterocyclic ring being saturated or unsaturated and optionallycontaining one or more hetero ring members (eg O, N or S) in addition tothe oxygen atom illustrated and the bicyclic oxygen radical beingoptionally substituted by one or more substituents such as thesubstituents mentioned above in connection with "aryl". A preferredexample of such a bicyclic oxygen radical is an optionally substitutedradical of the formula ##STR4##

Preferably R¹ is a phenyl radical containing a substituent in the orthoposition. A particularly preferred example of R¹ iso-(lower)alkoxyphenyl eg o-methoxyphenyl.

The term "heteroaryl" refers to an aromatic radical containing one ormore hetero ring atoms (eg oxygen, nitrogen, sulphur) and which may beoptionally substituted by one or more substituents. Examples of suitablesubstituents are given above in connection with "aryl" radicals. Theheteroaryl radical may, for example, contain up to 10 ring atoms.Preferably the heteroaryl radical is a monocyclic radical containing 5to 7 ring atoms. Preferably the hetero ring contains a nitrogen heteroatom with or without one or more further hetero atoms. When R¹ is aheteroaryl group it is preferably an optionally substituted pyrimidyl,quinolinyl, isoquinolinyl, or indolyl radical.

Preferred compounds have the following substituents either independentlyor in combination:

(a) R is hydrogen

(b) R¹ is aryl, for example o-(lower)alkoxyphenyl (eg o-methoxyphenyl)or bicyclic heteroaryl (eg indolyl)

(c) R² is hydrogen

(d) R³ is cycloalkyl, particularly cyclohexyl

(e) A is --CH₂ -- or --CH₂ CH₂ --

(f) X is --CO--, --CHOH--, --S--, --SO₂ -- or --CH₂ --.

The compounds of the invention may be prepared by methods known in theart from known starting materials or starting materials that may beprepared by conventional methods.

One method of preparing the compounds of the invention comprisesalkylating a piperazine derivative of formula ##STR5## with analkylating agent providing the group ##STR6##

The alkylating agent may be, for example, a compound of formula ##STR7##where R², R³, R⁴, X and A are as defined above and Z is a leaving groupsuch as halogen or an alkyl- or aryl-sulphonyloxy group.

The compounds of formula (I) in which X is --CHOH--, --S-- or --CH₂ --may also be prepared by reduction of an amide of formula ##STR8## whereR, R¹, R², R³, and R⁴ are as defined above and X is --CHOH--, --S-- or--CH₂ -- and A¹ is an alkylene radical of 1 or 2 carbon atoms optionallysubstituted by one or more (lower)alkyl groups. The reduction may, forexample, be carried out with a hydride transfer agent e.g.borane-dimethylsulphide or lithium aluminium hydride. The starting amideof formula (V) may be made by acylating a piperazine derivative offormula (II) above with an acylating derivative of an acid or formula##STR9##

The acylating derivative may be, for example, the acid chloride.

Another method of preparing the compounds of the invention wherein X is--CR⁵ OH--, --CH₂ -- or a single bond comprises reacting a compoundhaving the anion ##STR10## with a compound of formula ##STR11## where R²and R³ are as defined above, m is 0 or 1 and Y is a leaving group suchas halogen. Reaction of the aldehyde or ketone (VIIIa) with the aniongives a compound of the invention in which X is CR⁵ OH while reaction ofthe compound (VIIIb) with the anion gives a compound of the invention inwhich X is CH₂ or a single bond. The anion (VII) may be prepared byknown methods. For example the anion may be prepared by reacting thecompound ##STR12## with a base e.g. n-butyl lithium.

Compounds of the invention in which X is --CO-- may be prepared byoxidation of compounds in which X is --CHOH-- and compounds of theinvention in which X is --CHOH-- or --CH₂ -- may be prepared byreduction of compounds in which X is --CO--.

Compounds of the invention in which X is S may be prepared by reactingthe union (VII) as defined above with a compound of formula R³--S--S--R³ (eg isopropyldisulphide or cyclohexyldisulphide). Compoundsof the invention in which X is S may be oxidised to compounds of theinvention in which S is SO or SO₂. The oxidation may be carried out witha peroxidising agent (eg hydrogen peroxide).

If in any of the other processes mentioned herein, a substituent on thegroup R 1 is other than the one required the substituent may be convenedto the desired substituent by known methods.

The processes described above may be carried out to give a compound ofthe invention in the form of a free base or as an acid addition salt. Ifthe compound of the invention is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid additionsalt. Conversely, if the product of the process is a free base an acidaddition salt, particularly a pharmaceutically acceptable acid additionsalt, may be obtained by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds.

Examples of acid addition salts are those formed from inorganic andorganic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric,tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic,p-toluenesulphonic, oxalic and succinic acids.

The compounds of the invention contain an asymmetric carbon atom, sothat the compounds can exist in different steroisomeric forms. Thecompounds can be for example, racemates or optically active forms. Theoptically active forms can be obtained by resolution of the racemates orby asymmetric synthesis.

The compounds of the present invention possess pharmacological activity.In particular, they act on the central nervous system by binding to 5-HTreceptors. In pharmacological testing it has been shown that thecompounds particularly bind to receptors of the 5-HT_(1A) type. Ingeneral, the compounds selectively bind to receptors of the 5-HT_(1A)type to a much greater extent than they bind to other receptors such asα₁ and D₂ receptors. Many exhibit activity as 5-HT_(1A) antagonists inpharmacological testing. The Compounds of the invention can be used forthe treatment of CNS disorders, such as anxiety in mammals, particularlyhumans. They may also be used as antidepressants, antipsychotics,hypotensives and as agents for regulating the sleep/wake cycle, feedingbehaviour and/or sexual function and as cognition enhancing agents.

The compounds of the invention were tested for 5-HT_(1A) receptorbinding activity in rat hippocampal membrane homogenate by the method ofB. S. Alexander and M. D. Wood, J Pharm Pharmacol, 1988, 40, 888-891.The results for representative compounds of the invention are asfollows:

    ______________________________________                                               Compound                                                                              IC.sub.50 (nM)                                                 ______________________________________                                               Example 1a                                                                            4                                                                     Example 1b                                                                            4.3                                                                   Example 2a                                                                            2.0                                                                   Example 2b                                                                            1.8                                                                   Example 3                                                                             2.6                                                                   Example 4                                                                             1.6                                                                   Example 5                                                                             40                                                                    Example 6                                                                             4.25                                                                  Example 7                                                                             15                                                             ______________________________________                                    

The compounds are tested for 5-HT_(1A) receptor antagonism activity in atest involving the antagonism of 5-carboxamidotryptamine in theguinea-pig ileum in vitro (based upon the procedure of Fozard et al, BrJ Pharmac, 1985, 86, 601P).

The invention also provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable acid additionsalt thereof in association with a pharmaceutically acceptable carrier.Any suitable carrier known in the art can be used to prepare thepharmaceutical composition. In such a composition, the carrier isgenerally a solid or liquid or a mixture of a solid or liquid.

Solid form compositions include powders, granules, tablets, capsules(e.g. hard and soft gelatine capsules), suppositories and pessaries. Asolid carrier can be, for example, one or more substances which may alsoact as flavouring agents. lubricants. solubilisers. suspending agents,fillers, glidants, compression aides, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders the carrieris a finely divided solid which is in admixture with the finely dividedactive ingredient.

In tablets the active ingredient is mixed with a carrier having thenecessary compression properties in suitable proportions and compactedin the shape and size desired. The powders and tablets preferablycontain up to 99%, e.g. from 0.03 to 99%, preferably 1 to 80% of theactive ingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

The ten "composition" is intended to include the formulation of anactive ingredient with encapsulating material as carrier to give acapsule in which the active ingredient (with or without other carriers)is surrounded by the carrier, which is thus in association with it.Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions,emulsions, syrups, elixirs and pressurised compositions. The activeingredient, for example, can be dissolved or suspended in apharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both or pharmaceutically acceptable oils or fats.The liquid carrier can contain other suitable pharmaceutical additivessuch as solubilisers, emulsifiers, buffers, preservatives, sweeteners,flavouring agents, suspending agents, thickening agents, colours,viscosity regulators, stabilisers or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above, e.g. cellulose derivatives,preferably sodium carboxymethyl cellulose solution, alcohols, e.g.glycerol and glycols) and their derivatives, and oils (e.g. fractionatedcoconut oil and arachis oil). For parenteral administration the carriercan also be an oily ester such as ethyl oleate and isopropyl myristate.Sterile liquid carriers are used in sterile liquid form compositions forparenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. When the compound is orally active it can beadministered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form e.g. astablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged composition, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquid. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compostions inpackage form. The quantity of the active ingredient in unit dose ofcomposition may be varied or adjusted from 0.5 mg or less to 750 mg ormore, according to the particular need and the activity of the activeingredient.

The following Examples illustrate the invention:

EXAMPLE 1 (a) R*, R*-1-(2Methoxyphenyl)-4-(2-propan-(2-pyridinyl)-3-cyclohexyl)-3-ol!piperazine

and

(b) R*, S*-1-(2-Methoxyphenyl)-4-(2-propan-(2-pyridinyl)-3-cyclohexyl)-3-ol!piperazine

To a solution of 1-(2-methoxyphenyl)-4-(2-pyridinylethyl)piperazine(8.11 g, 27.3 mmol) in THF (anhydrous, 50 ml) at -78° C. under argon wasadded with stirring n-BuLi (23.8 ml, 1.26M).The addition was at such arate as to maintain an internal temperature of -75° C. or below. Thesolution was stirred at -78° C. for 15 minutes. The aldehyde,1-formylcyclohexane, (3.36 g, 30 mmol) in THF (10 ml) was addeddropwise. Water (1 ml) in THF 5 ml) was added in one portion after fiveminutes and the solution allowed to warm to room temperature. Thesolvent was removed and the residue dissolved in chloroform (30 ml). Theproducts were removed by washing with HCl (1N, 500 ml). The acidicextract was washed with ether and then adjusted to pH 12 by the additionof solid sodium hydroxide and cooling. The basic solution was extractedwith chloroform, washed with saturated salt solution, dried (MgSO₄)filtered and reduced to a viscous oil (11.0 g).

The diastereomeric alcohols were separated by silica gel columnchromatography using ether as eluant. The least polar component was thetitle compound (a) and the hydrochloride was obtained by dissolving inchloroform and adding ethereal HCl. Recrystallisation from methanol andether gave the title compound (a) hydrochloride, m.p. 155°-156° C.

C₂₅ H₃₅ N₃ O₂.2.5HCl.2H₂ O requires: C, 55.94; H, 7.79; N, 7.83%. Found:C, 56.14; H, 7.58; N, 7.71%.

The more polar component was the title compound 1(b) and this wasconverted to the hydrochloride. Crystallisation from methanol/ether gavethe title compound (b) hydrochloride, m.p. 135°-136° C.

C₂₅ H₃₅ N₃ O₂.3HCl.H₂ O requires: C. 55.92: H. 7.51: N. 7.83% Found: C.55.64: H. 7.45: N. 7.71%.

EXAMPLE 2 (a) R*,R*-1-(2-Methoxyphenyl)-4-3-butan-(2-pyridinyl)-4-cyclohexyl)-4-ol!piperazine

and

(b) R*,S*-1-(2-Methoxyphenyl)-4-3-butan-(2-pyridinyl)-4-cyclohexyl)-4-ol!piperazine

To a cooled (-78° C. internal) solution of 1-(2-methoxyphenyl)-4-(3-pyridinylpropyl)piperazine (2.15 g, 6.63 mol) underargon in THF (15 ml) was added with stirring n-BuLi (5.78 ml, 126M) atsuch a rate that the temperature did not rise above -60° C. (internal).The solution of the anion was stirred at -78° C. for fifteen minutes.The aldehyde, 1-formylcyclohexane, (0.803 ml, 6.63 mol) in THF (2 ml)was added. After approximately fifteen minutes water was added and thereaction allowed to come to room temperature.

The solvents were removed and the residue portioned between chloroformand water. The organic layer was washed with sat. salt solution, dried(MgSO₄) and reduced to a viscous oil following filtration. The residuewas purified by silica gel column chromatography under pressure elutingwith ether. The two diastereomeric products were separated by repeatedcolumn chromatography to yield samples of the two title compounds.

The least polar diastereomer was converted to its hydrochloride saltgiving the title compound (a) hydrochloride, m.p. 128°-129° C.

C₂₆ H₃₇ N₃ O₂.2HCl.1.1.75H₂ O requires: C, 59.14; H, 8.11; N, 7.96%.Found: C, 59.14; H, 7.91; N, 7.84%.

The more polar diastereomer was convened to its hydrochloride gave thetitle compound (b) hydrochloride, m.p. 108°-109° C.

C₂₆ H₃₇ N₃ O₂.2HCl.2.25H₂ O requires: C. 58.15: H. 8.16: N. 7.82%.Found: C. 58.26: H. 7.75: N. 7.78%.

EXAMPLE 3 1-(2-methoxyphenyl-4- 3-(2-pyridinyl)-4-(cyclohexyl-4- one)butyl!piperazine

The diastereomeric mix of 1-(2-methoxyphenyl)4-3-butan-(2-pyridinyl)4-cyclohexyl)4-ol!piperazine from Example 2 (1.23g, 2.91 mmol) was dissolved in dry dichloromethane (5 ml). This wasadded to a preformed solution of oxalyl chloride (292 ml, 3.35 mmol) anddimethyl sulphoxide (539 ml, 7 mmol) in dichloromethane (dry 75 ml) at-60° C. (internal), over 2 minutes. Following the addition the reactionmixture was stirred at between -50° and -6° C. for fifteen minutes.Triethylamine (2 ml, 14.5 mmol) was added and the reaction allowed toreach 0° C. Dichloromethane (50 ml) was added and the reaction mixturewas washed with water and brine and then dried (MgSO₄). The organicsolvent was removed in vacuo to give an oil. The residue was purified bypressure silica gel column chromatography using ether as eluant. The oil(1.0 g) was dissolved in chloroform and ethereal HCl added to give thetitle compound as the hydrochloride, m.p. 102°-104° C.

C₂₆ H₃₅ N₃ O₂.3HCl.1.75H₂ O requires: C, 55.52; H, 7.44; N, 7.47%.Found: C, 55.57; H, 6.93; N, 7.31%.

EXAMPLE 4 1-(2-Methoxyphenyl)-4-(4-(cyclohexyl)-3-(2-pyridinyl)butyl!piperazine

To a solution of 1-(2-methoxyphenyl)4-(3-pyridinylpropyl)piperazine (1.0g, 3.1 mmol) at 0° C. in dry toluene (10 ml) was added n-BuLi (3.9 ml).After a further 10 minutes at 0° C. the suspension was treated withcyclohexylmethyl bromide (0.649 ml, 4.7 mmol). The reaction was allowedto stir at 0° C. for a further 2 hours.

The product was extracted into 1N HCl. The aqueous layer was separated,washed with ether and basified (solid NaOH). The basic aqueoussuspension was washed with chloroform (2×70 ml). The organic layer waswashed with salt solution, dried (MgSO₄) and filtered. Removal of thesolvent gave a yellow oil which was purified by pressure silica gelcolumn chromatography using ether as eluant (690 mg). The material wassubjected to further chromatography using hexane/ether (1:2) as eluantto give the title compound.

The HCl salt, m.p. 110°-111° C. was prepared by dissolving the free basein chloroform and adding ethereal HCl.

C₂₆ H₃₇ N₃ O.2HCl.1.25H₂ O requires: C, 62.08; H, 8.32; N, 8.35%. Found:C, 62.34; H, 8.21; N, 8.23%.

EXAMPLE 5 1-(2-Methoxyphenyl)-4-1-((1-methyl)thioethyl)-1-(2-pyridinyl)ethyl!piperazine

1-(2-Methhoxyphenyl)-4- 1-(2-pyridinyl)ethyl!piperazine (2.974 g, 10mmol) was dissolved in anhydrous THF (25 ml) and the solution cooled to-70° C., n-butyl-lithium (1.6M solution, 7 ml, 11 mmol) was addeddropwise. After 10 mins, isopropyl disulphide (1.50 g, 10 mmol) in THF(5 ml) was added and the reaction mixture allowed to warm to roomtemperature over 2 h. The mixture was poured into water (100 ml),extracted with dichloromethane (3×100 ml), washed with brine (100 ml),dried (Na₂ SO₄), and concentrated in vacuo. The residue was filteredthrough a plug of silica to give a colourless oil which was dissolved inether and treated with ethanolic hydrogen chloride to afford the titlecompound as trihydrochloride 0.25 hydrate (0.54 g), m.p. 127°-131° C.

(Found: C,51.9; H, 6.9; N, 8.8. C₂₁ H₂₉ N₃ OS.3HCl.0.25HCl.0.25H₂ Orequires C, 52.0; H, 6.75; N, 8.7%).

EXAMPLE 6 1-(2-Methoxyphenyl)-4-3-(cyclohexylthio)-3-(2-pyridinyl)propyl!piperazine

To a solution of 1-(2-methoxyphenyl)-4-(3- pyridylpropyl)piperazine(5.13 g, 0.0158 mol) in dry toluene (50 ml) under argon, at an internaltemperature of -13° C. was added nBuLi (15.81 ml, 17.39 mmol). Thetemperature was maintained below -3° C.

After stirring and warming to 0° C. cyclohexyldisulphide (4.0 g. 17.37mmol) was added over 15 minutes.

The solution was stirred at room temperature for 2 hours. Water wasadded followed by HCl (1N). The volatiles were removed and the aqueousacid layer washed with ethyl acetate. The acid layer was basified withsodium hydroxide (solid) with cooling and the layer extracted with ethylacetate several times.

The organic layer thus obtained was washed with saturated NaCl followedby drying with MgSO₄. After filtration the solvent was removed and theresidue purified by silica gel pressure column chromatography elutingwith chloroform/methanol (20/l).

The title compound was obtained (3.6 g) and convened to dihydrochloridedihydrate (m.p. 113°-15° C.).

C₂₅ H₃₅ N₃ OS.2HCl.2H₂ O requires C, 56.17; H, 7.73; N, 7.82%. Found: C,55.99; H, 7.98; N, 7.58%.

EXAMPLE 7 1-(2-Methoxyphenyl)-4-3-(cyclohexylsulphoxy)-3-(2-pyridinyl)propyl!piperazine

To a solution of the sulphide from Example 6 (2.16 g, 5.08 mmol) inacetic acid (15 ml) at room temperature under argon was added withstirring H₂ O₂ (1.51 ml, 27.5%).

After 6 hours at room temperature a further 0.2 ml of H₂ O₂ was addedand the solution placed in the refrigerator for 48 hours.

The solvent was removed and the residue poured into sodium bicarbonatesolution. The product was extracted with dichloromethane, washed withNaGl solution, dried (MgSO₄) and filtered. Removal of the solvent gave ayellow oil which was purified under pressure by elution of a silica gelcolumn with chloroform/methanol (50/1). Of the two diastereomericproducts thus obtained the least polar material was recolumned to givethe title product (300 mg). The HCl salt, m.p. 130°-132° C. was preparedby dissolving the sulphoxide in chloroform and adding ethereal HCl.

C₂₅ H₃₅ N₃ O₂ S.3HCl.2.75H₂ O requires C, 50.00; H, 7.30: N, 7.00%.Found C. 49.91: H. 7.58: N. 7.07%.

EXAMPLE 8 1-(2-Methoxyphenyl)-4-3-(cyclohexylsulphonyl)-3-(2-pyridinyl)propyl!piperazine

To a stirred solution of 1-(2-methoxyphenyl)-4-3-(cyclohexylthio)-3-(2-pyridinyl)propyl!piperazine at room temperaturewas added N-methylmorpholine N-oxide (0.351 g, 3 mmol) followed by asolution of osmium tetroxide in t-butanol (2.5% wt, 630 ml). Aftereighteen hours sodium metabisulphite (sat.) was added and the reactionmixture stirred vigorously.

The organic material was extracted into chloroform, washed with brine,dried (MgSO₄) and filtered. Following removal of the solvent the oil waspurified by pressure silica gel column chromatography eluting with agradient of chloroform/methanol 50/1 20/1/.

The product (340 mg) was dissolved in chloroform/ether and ethereal HCladded. The title compound was obtained as the hydrochloride, anoff-white solid, m.p. 135°-137° C.

C₂₅ H₃₅ N₃ O₃ S.2HCl.1.75H₂ O requires: C, 53.42; H, 7.26; N, 7.48%.Found C, 53.42; H, 7.15; N, 7.46%.

EXAMPLE 9 1-(2-Methoxyphenyl)-4-5-(cyclohexyl)-3-(2-pyridinyl)pentyl!piperazine

The title compound was prepared following the procedure of Example 4using cyclohexylethyl bromide as reactant in place of cyclohexylmethylbromide. The product was obtained as the hydrochloride, m.p. 134°-135°C.

C₂₇ H₃₉ N₃ O.3HCl.0.5CH₃ 0H requires: C, 60.38: H, 8.11; N. 7.68%. FoundC, 60.28; H, 8.28; N, 7.88%.

EXAMPLE 10 1-(2-Methoxyphenyl)-4-2-(cyclohexylthio)-2-(2-pyridinyl)ethyl!piperazine

The title compound was prepared following the procedure of Example 5using cyclohexyl disulphide as a reactant in place of isopropyldisulphide. The product was obtained as the hydrochloride, m.p. 91°-92°C.

C₂₄ H₃₃ N₃ OS.3HCl.1.25H₂ 0 requires: C, 53.04; H, 7.14; N, 7.73%. FoundC, 53.08; H, 7.29; N, 7.61%.

EXAMPLE 11 1-(2-Methoxyphenyl)-4-3-(cyclopentylthio)-3-(2-pyridinyl)propyl!piperazine

The title compound was prepared following the procedure of Example 6using cyclopentyl disulphide as reactant in place of cyclohexyldisulphide. The product was obtained as the hydrochloride, m.p. 95°-97°C.

C₂₄ H₃₃ N₃ OS.2HCl.1.5H₂ 0 requires: C, 56.35; H, 7.49; N, 8.21%. FoundC, 56.17; H, 7.60; N, 8.12%.

EXAMPLE 12 1-(2-Methoxyphenyl)-4-3-(cyclopentylsulphonyl)-3-(2-pyridinyl)propyl!piperazine

The title compound was prepared following the procedure of Example 8using 1-(2-methoxyphenyl)-4-3-(cyclopentylthio)-3-(2-pyridinyl)propyl!piperazine as the startingmaterial. The product was obtained as the hydrochloride, m.p. 145°-146°C.

C₂₄ H₃₃ N₃ O₃ S.2HCl.2H₂ 0 requires: C, 52.17; H. 7.11; N. 7.60%. FoundC, 52.25: H, 7.01; N, 7.71%.

EXAMPLE 13 1-(2-Methoxyphenyl)-4-2-(cyclohexylsulphonyl)-2-(2-pyridinyl)ethyl!piperazine

The title compound was prepared following the procedure of Example 8using 1-(2-methoxyphenyl)-4-2-(cyclohexylthio)-2-(2-pyridinyl)ethyl!piperazine as the startingmaterial. The product was obtained as the hydrochloride, m.p. 75°-76° C.

C₂₄ H₃₃ N₃ O₃ S.3HCl.2H₂ 0 requires: C, 50.48; H, 6.71; N, 7.36%. FoundC, 50.48; H, 6.80; N, 7.14%.

EXAMPLE 14 1-(2-Methoxyphenyl)-4-3-(cyclohexyl)-3-(2-pyridinyl)propyl!piperazine

To a dry toluene (14 ml) solution of1-(2-methoxyphenyl)-4-(3-pyridinylpropyl)piperazine (1.5 g, 4.82 mmol)under argon at 0° C. was added nBuLi (7.4 ml, 1.3M). After anionformation the solution was treated with cyclohexylbromide (1.18 ml, 9.64mmol) in toluene (2.8 ml). The reaction mixture was allowed to attainroom temperature and stirred overnight. The reaction mixture was treatedwith HCl (1N) and the organic layer discarded. The acid layer was washedwith ether, taken to pH 13 with solid NaOH (cool) and extracted withchloroform.

The organic layer was washed with sat NaCl solution, dried (MgSO₄)filtered and reduced to an oil.

The product was eluted from a silica gel pressure column with ethylacetate and convened to the hydrochloride salt, m.p. 140°-142° C.

C₂₅ H₃₅ N₃ O.3HCl.1.25H₂ 0 requires: C, 57.14; H. 7.77: N. 8.00%. FoundC. 57.27; H, 7.82; N, 7.94%.

EXAMPLE 15 1-(2-Methoxyphenyl)-4-3-butan-(2-pyridinyl-4-dicyclohexyl-4-ol!piperazine

To a solution of 1-(2-methoxyphenyl)4-(3-pyridinylpropyl)piperazine (3.0g, 9.24 mmol) in anhydrous toluene (30 ml) was added, under argon withstirring at 0° C., nBuLi (7.8 ml, 1.3M). After twenty minutesdi(cyclohexane) ketone (2.36 ml, 12 mmol) was added and the reactionstirred at room temperature for 13 hours.

1N HCl was added and a grey precipitate removed by filteration. Theaqueous layer was washed with dichloromethane, taken to pH 13 by theaddition of solid sodium hydroxide (with cooling). The organic materialwas extracted into ethylacetate, washed with brine, dried (MgSO₄),filtered and reduced to an oil.

The residue was purified by pressure silica gel column chromatography togive the title compound which was convened to the HCl salt, m.p.175°-176° C., with ethereal HCl.

C₃₂ H₄₇ N₃ O₂.3HCl.1.5H₂ 0 requires: C, 59.85; H, 8.32; N, 6.54%. FoundC, 60.02; H, 8.34; N, 6.53%.

We claim:
 1. A compound of general formula ##STR13## or apharmaceutically acceptable acid addition salt thereof wherein Rrepresents hydrogen or one or two same or different C₁ -C₆ alkylgroupsR¹ is mono or bicyclic aryl selected from phenyl, naphthyl andbezodioxan-5-yl, each optionally substituted by one or more substituentsselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl, nitro,nitrile, (C₁₋₆)alkoxycarbonyl, amino, mono(C₁₋₆)alkylamino anddi(C₁₋₆)alkylamino, or R¹ is mono or bicyclic heteroaryl selected frompyrimidinyl, quinolinyl, isoquinolinyl, and indolyl, each optionallysubstituted by one or more substituents selected from C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, halo(C₁₋₆)alkyl, nitro, nitrile, (C₁₋₆)alkoxycarbonyl,amino, mono(C₁₋₆)alkylamino and di(C₁₋₆)alkylamino R² is hydrogen or C₁-C₆ alkyl R³ is hydrogen or cycloalkyl R⁴ is hydrogen or C₁ -C₆ alkyl Ais an alkylene chain of 1 to 3 carbon atoms optionally substituted byone or more lower alkyl groups and X is --CO--, --CR⁵ OH-- (where R⁵ ishydrogen, C₁ -C₆ alkyl or cycloalkyl), S, SO or SO₂ or X can also be--(CH₂)_(n) -- (where n is 0, 1 or 2) when R³ is cycloalkyl.
 2. Acompound as claimed in claim 1 in which R¹ is monocyclic aryl orbicyclic heteroaryl.
 3. A compound as claimed in claim 1 in which R³ iscyclohexyl.
 4. A compound as claimed in claim 1 in which X is --CO--.--CHOH--, --S--, --SO₂ -- or --CH₂ --.
 5. A compound as claimed in claim1 which isR *, R*-1-(2-methoxyphenyl)-4-(2-propan-(2-pyridinyl)-3-cyclohexyl)-3 -ol!piperazine, R*,S*-1-(2-methoxyphenyl)4-(2-propan-(2-pyridinyl)-3-cyclohexyl)-3-ol!piperazine, R*,R*-1-(2-methoxyphenyl)4-3-butan-(2-pyridinyl)4-cyclohexyl)4-ol!piperazine R*,S*-1-(2-methoxyphenyl)4-3-butan-(2-pyridinyl)4-cyclohexyl)-4-ol!piperazine,1-(2-methoxyphenyl-4- 3-(2-pyridinyl)4-cyclohexyl4-one!piperazine,1-(2-methoxyphenyl)-4- 4-(cyclohexyl)-3-(2-pyridinyl)butyl!piperazine,1-(2-methoxyphenyl)-4- 1-((1-methyl)thioethyl)-1-(2-pyridinyl)ethyl!piperazine,1-(2-methoxyphenyl)-4-3-(cyclohexylthio)-3-(2-pyridinyl)propyl!piperazine,1-(2-methoxyphenyl)-4-3-(cyclohexylsulphoxy)-3-(2-pyridinyl)propyl!piperazine,1-(2-methoxyphenyl)-4-3-(cyclohexylsulphonyl)-3-(2-pyridinyl)propyl!piperazine,1-(2-methoxyphenyl)-4- 5-(cyclohexyl)-3-(2-pyridinyl)pentyl!piperazine,1-(2-methoxyphenyl)-4-2-(cyclohexylthio)-2-(2-pyridinyl)ethyl!piperazine,1-(2-methoxyphenyl)-4-3-(cyclopentylthio)-3-(2-pyridinyl)propyl!piperazine1-(2-methoxyphenyl)-4-3-(cyclopentylsulphonyl)-3-(2-pyridinyl)propyl!piperazine,1-(2-methoxyphenyl)-4-2-(cyclohexylsulphonyl)-2-(2-pyridinyl)ethyl!piperazine,1-(2-methoxyphenyl)-4- 3-(cyclohexyl)-3-(2-pyridinyl)propyl!piperazineor 1-(2-methoxyphenyl)-4-3-butan-(2-pyridinyl)-4-dicyclohexyl-4-ol!piperazine or apharmaceutically acceptable acid addition salt thereof.
 6. Apharmaceutical composition for use as a 5HT_(1A) antagonist comprising acompound claimed in claim 1 in association with a pharmaceuticallyacceptable carrier.